Association Between Hemoglobin-to-Red Blood Cell Distribution Width Ratio and 30-Day Mortality in Patients with Acute Pancreatitis: Data from MIMIC-III and MIMIC-IV

Background/Aims: To investigate the relationship between hemoglobin-to-red blood cell distribution width (RDW) ratio (HRR) and the 30-day mortality risk in acute pancreatitis (AP), and assess the predictive ability of HRR. Materials and Methods: Data from 2001 to 2019 in the Medical Information Mart for Intensive Care-III/IV (MIMIC-III/IV) were analyzed. The outcome of this retrospective cohort study was 30-day mortality. Hemoglobin-to-RDW ratio (0-24 hours) and HRR (24-48 hours) were divided into 4 groups based on quartiles (Q1, Q2, Q3, and Q4). The predictive effect was evaluated by the C-index. Results: A total of 1736 patients were included, and 30-day mortality occurred in 204 (11.75%) patients. Compared with Q1 of HRR (0-24 hours), Q2 (HR = 0.60, 95% CI : 0.42-0.86), Q3 (HR =0.47, 95% CI : 0.31-0.71), and Q4 (HR = 0.45, 95% CI : 0.29-0.68) of HRR levels reduced the 30-day mortality risk. Hemoglobin-to-RDW ratio (24-48 hours) was consistent with the results of HRR (0-24 hours). For changes in HRR, Q4 for changes in HRR levels (HR = 1.64, 95% CI : 1.09-2.45) increased the 30-day mortality risk. Hemoglobin-to-RDW ratio significantly improved the predictive effect of Sequential Organ Failure Assessment (C-index = 0.736) and Bedside Index of Severity in Acute Pancreatitis (C-index = 0.704) on 30-day mortality. Conclusion: Higher HRR levels reduced the 30-day mortality risk in AP and may improve the prediction of other tools.


INTRODUCTION
Acute pancreatitis (AP), an unpredictable and possibly deadly disease, is one of the primary causes of hospitalization for gastrointestinal diseases, with around 300 000 emergency visits annually. 1,24][5] Moderate to severe AP occurs in about 2% of patients, characterized by pancreatic or peripancreatic tissue necrosis or organ failure, with a mortality rate of 20%-40%. 6The discovery of simple and accurate indicators to predict the risk of death in AP patients exhibits important clinical significance.
8][9] Evidence showed that AP patients with anemia had higher severity, a greater incidence of acute kidney injury (AKI), and longer hospital stays compared to patients without anemia.This may be due to organ hypoxia caused by a decrease in blood oxygen-carrying capacity. 10 However, the predictive effect of hemoglobin levels for the death risk in AP patients is unclear.In addition to anemia, systemic inflammation is an important pathological mechanism that affects the prognosis of AP patients.Red blood cell distribution width (RDW) can be used as an inflammatory marker in the prognostic assessment of cardiovascular disease, cancer, and other diseases. 11,12t present, limited small-sample studies reported that elevated RDW levels in AP patients increased the risk of short-term death. 13,14Moreover, the high production of cytokines during inflammation limits iron absorption and inhibits red blood cell (RBC) maturation, which further contributes to anemia. 157][18][19] Nevertheless, the relationship between HRR and the risk of death in AP patients is unclear.
We intended to analyze the correlation between HRR and the 30-day mortality risk in AP patients, and evaluate the predictive value of HRR with the data from Medical Information Mart for Intensive Care (MIMIC) databases.

MATERIALS AND METHODS Sources of Data
Data on AP patients were obtained from 2001 to 2019 in the MIMIC-III/IV databases.Medical Information Mart for Intensive Care contains data on patients admitted to the intensive care unit (ICU) at the Beth Israel Deaconess Medical Center: demographic data, vital sign measurements, laboratory results, etc. Medical Information Mart for Intensive Care-III covered data on more than 40 000 patients between 2001 and 2012; MIMIC-IV comprised data on over 300 000 patients from 2008 and 2019 (https ://mi mic.m it.edu/doc s/abo ut/).The requirement of ethical approval for this was waived by the Institutional Review Board of Huashan Hospital, Fudan University because the data was accessed from MIMIC-III/IV (publicly available databases).The need for written informed consent was waived by the Institutional Review Board of Huashan Hospital, Fudan University due to the retrospective nature of the study.

Follow Up
Follow-up started 24 hours after the initial ICU admission and ended 30 days after the initial ICU admission or at the time of death.Information on in-hospital mortality was obtained through hospital records.Information on out-of-hospital mortality was obtained from the Social Security Administration Death Master File (https ://ph ysion et.or g/con tent/ mimic iii/1 .4/).

Statistical Analysis
Continuous data with a normal distribution were reported by mean ± standard deviation (mean ± SD), and the

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The relationship between the hemoglobin-to-RDW ratio (HRR) and the 30-day mortality risk in acute pancreatitis (AP) patients was analyzed for the first time.

Association Between HRR and 30-day Mortality in Subpopulations
Stratified analysis was further conducted in subpopulations with hypertension, diabetes, respiratory failure, AKI, renal failure, liver cirrhosis, sepsis, or malignant tumor (Figure 4).

Renal Failure
In patients with renal failure, no significant association was found between HRR and 30-day mortality (P > .05).

DISCUSSION
The relationship between HRR and 30-day mortality risk in AP patients was explored, and the value of HRR in predicting 30-day mortality was assessed.The findings demonstrated that decreased HRR (0-24 hours) and HRR (24-48 hours) levels increased the 30-day mortality risk.For changes in HRR at 0-24 and 24-48 hours after admission, only patients in the Q4 group were linked to a higher 30-day mortality risk (vs.Q1).In addition, HRR significantly improved the predictive effect of SOFA and BISAP on 30-day mortality in AP patients.
As an indicator incorporating hemoglobin and RDW, HRR has emerged as a new biomarker associated with mortality in many diseases.High HRR levels at admission were associated with lower long-term mortality in patients with sepsis. 20Huang et al 21 showed that lower HRR was correlated with a greater mortality risk among patients with sepsis-associated encephalopathy.According to another study, HRR was predictive of HBV-related decompensated cirrhosis. 16An inverse relationship was observed between HRR and event-free survival in head and neck cancer, as illustrated by Tham et al.'s study. 22ur results demonstrated that decreasing HRR levels increased the 30-day mortality risk in AP patients.The potential mechanism of the association between HRR and 30-day mortality is still uncertain.Among individuals with AP, an inflammatory disorder of the pancreas, 23 RDW, which can reflect the inflammatory state, was observed to be corelated with mortality. 24,25As a possible explanation, bone marrow function and iron metabolism may be affected by inflammation.Inflammatory cytokines inhibit the maturation of RBCs, making newer and larger reticulocytes participate in the circulation, which is related to increased RDW. 26 High oxidative stress also decreases erythrocyte survival, prompting the release of large numbers of prematurely maturing erythrocytes into the peripheral circulation, leading to increased RDW.In addition, inflammation affects erythrocyte membrane glycoproteins and ion channels, leading to changes in erythrocyte morphology. 27,28These conditions may be linked to the death risk in AP patients.Furthermore, hemoglobin, the other parameter of HRR, reflects the severity and prognosis of AP patients.Lin et al 29 found that hypertriglyceridemic AP patients with varying grades     of severity had different levels of hemoglobin.A negative association between hemoglobin and mortality in AP was exhibited by another study, 30 which supported the findings of this study.Anemia may play a role in the correlation between hemoglobin and 30-day mortality.Less oxygen will be transported to major organs under a low level of hemoglobin, resulting in organ hypoxia. 31This may promote multi-organ functional dysfunction, which might be associated with short-term mortality.Additionally, hemoglobin levels may be affected by inflammatory responses in several ways, such as inhibiting RBC generation, shortening RBC survival, and reducing the production of erythropoietin. 32 note, this study found that incorporating HRR into the SOFA or BISAP improved the predictive performance of the SOFA or BISAP, which confirmed the predictive ability of HRR in 30-day mortality among AP patients.The SOFA score evaluates organ dysfunction in the ICU, using data on PaO 2 /FiO 2 , platelets, bilirubin, hypotension, Glasgow Coma Scale, and renal function. 33Given the significant improvement in the predictive capability of the SOFA by HRR, HRR may be taken into account when assessing the 30-day mortality risk in AP, which may help improve prognoses of AP patients.Besides, in different subpopulations, the relationship between HRR and 30-day mortality varied.No significant association was found in AP patients with malignant tumor and renal failure, which may be attributed to the small sample size included for analysis.[36][37]  This research first probed the relationship between HRR and the 30-day mortality risk in AP patients and indicated the predictive value of HRR.Hemoglobin-to-RDW ratio, an easily accessible static indicator, serves as a good supplement to the SOFA.With consideration of HRR, clinicians may better predict the prognosis of AP patients and provide timely and personalized treatment strategies for prognosis improvement.Meanwhile, several limitations should be acknowledged.First, due to the retrospective study, selection bias may exist.Second, information on the diet and lifestyle of patients was not collected by MIMIC, and these possible confounding factors were not adjusted for.Third, the findings were obtained based on single-center data, which may limit the generalization of this study.Fourth, although we analyzed the effects of HRR levels and changes in 0-24 hours and 24-48 hours after admission on 30-day mortality, the relationship between changes in HRR over longer periods and patient mortality needs to be further explored.Fifth, the relationship between changes in HRR values after versus before pancreatitis and patient mortality may provide meaningful information, but HRR values before pancreatitis were not available due to database limitations.Sixth, detailed treatment information is an important factor in accurately assessing disease prognosis, but the absence of treatment information in the database may affect the accuracy of our results.
Decreasing HRR levels increased the 30-day mortality risk and exhibited good predictive ability in 30-day death prediction, indicating that consideration of HRR in clinical prediction of 30-day mortality may facilitate prognosis management in AP.These findings need to be verified in more studies.

Table 1 .
Characteristics of the Included Acute Pancreatitis Patients • Decreased HRR levels increased the 30-day mortality risk in AP patients.• HRR improved the prediction of other tools (e.g., SOFA and BISAP) for mortality in AP patients.t-test was applied to make comparisons between groups.within 2 days of ICU admission (n = 7), 1736 patients were enrolled.Of the included patients, 204 (11.75%) died within 30 days (non-survivors), while 1532 (88.25%) survived for 30 days or more (survivors).The process of study population selection is presented in Figure 1.The mean age was 58.93 years, and men accounted for 57.26% of the total population.Most patients were White.Table 1 lists the detailed characteristics of these AP patients.Survivors were significantly younger than non-survivors (P < .001).Moreover, significant differences were also found in ethnicity, mechanical ventilation, vasopressor, RRT, blood transfusion, congestive heart failure, atrial fibrillation, respiratory failure, AKI, liver cirrhosis, sepsis, malignant tumor, SBP, DBP, MAP, body temperature, respiratory rate, WBC, hematocrit, Figure 1.Process of study population selection.AP, acute pancreatitis; ICU, intensive care unit; MIMIC, Medical Information Mart for Intensive Care; RDW, red blood cell distribution width.Fasting glucose, mg/dL, M (Q 1 , Q 3 ) 126.00 (101.00,166.50) 125.00 (101.00,166.00) 129.50 (103.50, 169.50) .236

Table 1 .
Characteristics of the Included Acute Pancreatitis Patients (Continued)

Table 2 .
Cox Proportional Hazards Models for Screening Confounding Factors Associated with 30-day Mortality in Acute Pancreatitis (Continued)